prof. mariane de oliveira menezes (orcid id : 0000-0002 ... · prof. mariane de oliveira menezes...
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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1471-0528.16470 This article is protected by copyright. All rights reserved
PROF. MARIANE DE OLIVEIRA MENEZES (Orcid ID : 0000-0002-8525-0521)
Article type : Main research article
Title: Clinical characteristics and risk factors for mortality in obstetric patients with severe
COVID-19 in Brazil: a surveillance database analysis
Author’s and affiliations
1- Maira L.S. Takemoto, PhD. São Paulo State University (UNESP), Medical School of Botucatu.
Programa de Pós-graduação em Tocoginecologia. Address: Av. Prof. Montenegro, s/n - Botucatu -
SP, Brazil. Postal code: 18618-687.
2- Mariane O. Menezes, MSc. Programa de Pós-graduação em Tocoginecologia. São Paulo State
University (UNESP), Medical School of Botucatu. Address: Av. Prof. Montenegro, s/n - Botucatu
- SP, Brazil. Postal code: 18618-687.
3- Carla B. Andreucci, PhD. Universidade Federal de São Carlos (UFSCAR), Department of
Medicine. Address: Rodovia Washington Luis, km 235 - São Carlos - SP, Brazil. Postal code:
13565-905.
4- Roxana Knobel, PhD. Universidade Federal de Santa Catarina (UFSC), Department of
Gynecology and Obstetrics. Address: R. Eng. Agronômico Andrei Cristian Ferreira, s/n -
Trindade, Florianópolis - SC, Brazil. Postal code: 88040-900.
5- Liduína A.R. Sousa, MD. Programa de Pós-Graduação Profissional em Saúde da Mulher e da
Criança. Universidade Federal do Ceará (UFC). Address: Av. da Universidade, 2853 - Benfica,
Fortaleza - CE, Brazil. Postal code: 60020-18.
6- Leila Katz, PhD. Programa de Pós-graduação em Saúde Materno Infantil do IMIP. Instituto de
Medicina Integral Professor Fernando Figueira (IMIP). Address: R. dos Coelhos, 300 - Boa Vista,
Recife - PE, Brazil. Postal code: 50070-902. Acc
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This article is protected by copyright. All rights reserved
7- Eduardo B. Fonseca, PhD. Universidade Federal da Paraíba, Division of Obstetrics and
Gynecology. Address: Campus I - Lot. Cidade Universitaria, PB, Brazil. Postal code: 58051-900.
8- Marcos Nakamura-Pereira, PhD. Instituto Nacional de Saúde da Mulher, da Criança e do
Adolescente Fernandes Figueira, Fundação Oswaldo Cruz. Address: Av. Rui Barbosa, 716 –
Flamengo. Rio de Janeiro - RJ, Brazil. Postal code: 22250-020.
9- Claudia G. Magalhães, PhD. Department of Gynecology and Obstetrics. São Paulo State
University (UNESP), Medical School of Botucatu. Av. Prof. Montenegro, s/n - Botucatu - SP,
Brazil. Postal code: 18618-687.
10- Carmen S.G. Diniz, PhD. Department of Health, Life Cycles and Society, School of Public Health,
University of São Paulo. Address: Av. Dr. Arnaldo, 715 - Cerqueira César, São Paulo - SP, Brazil.
Postal code: 01246-904.
11- Adriana S.O. Melo, PhD. Departamento de Saúde da Mulher. Instituto de Pesquisa Professor
Joaquim Amorim Neto, IPESQ. Address: R. Salvino Oliveira Neto, 87 - Santo Antônio, Campina
Grande - PB, Brazil. Postal Code: 58402-040.
12- Melania M.R. Amorim, PhD. Programa de Pós-graduação em Saúde Materno Infantil do IMIP.
Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Address: R. dos Coelhos, 300 -
Boa Vista, Recife - PE, Brazil. Postal code: 50070-902.
(Brazilian Group for Studies of COVID-19 and Pregnancy)
Corresponding Author
13- Mariane O. Menezes, MSc. Programa de Pós-graduação em Tocoginecologia. São Paulo State
University (UNESP), Medical School of Botucatu. Address: Av. Prof. Montenegro, s/n - Botucatu
- SP, Brazil. Postal code: 18618-687. Telephone +55 (14) 3880-1001. E-mail:
Running Title: Risk factors for COVID-19 maternal death in Brazil
ABSTRACT
Objective: To describe clinical characteristics of pregnant and postpartum women with severe
COVID-19 in Brazil and to examine risk factors for mortality
Design: Cross-sectional study based on secondary surveillance database analysis
Setting: Nationwide BrazilAcc
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Population or Sample: 978 Brazilian pregnant and postpartum women notified as COVID-19
Acute Respiratory Distress Syndrome (ARDS) cases with complete outcome (death or cure) until
June 18, 2020
Methods: Data was abstracted from the Brazilian ARDS Surveillance System (ARDS-SS)
database. All eligible cases were included. Data on demographics, clinical characteristics,
intensive care resources use and outcomes were collected. Risk factors for mortality were
examined by multivariate logistic regression.
Main Outcome Measures: Case fatality rate
Results: We identified 124 maternal deaths, corresponding to a case fatality rate among COVID-
19 ARDS cases in the obstetric population of 12.7%. At least one comorbidity was present in
48.4% of fatal cases compared to 24.9% in survival cases. Among women who died, 58.9% were
admitted to ICU, 53.2% had invasive ventilation and 29.0% had no respiratory support. The
multivariate logistic regression showed that the main risk factors for maternal death by COVID-19
were postpartum at onset of ARDS, obesity, diabetes, and cardiovascular disease, while white
ethnicity had a protective effect.
Conclusions: Negative outcomes of COVID-19 in this population are affected by clinical
characteristics, but social determinants of health also seem to play a role. It is urgent to reinforce
containment measures targeting obstetric population and ensure high quality care throughout
pregnancy and postpartum period.
Funding: The study received no funding.
Keywords: COVID-19, Maternal Death, Health Services Accessibility, Health Status Indicators
Tweetable abstract
A total of 124 COVID-19 maternal deaths were identified in Brazil. Symptoms onset at
postpartum and comorbidities are risk factors.
INTRODUCTION
COVID-19 is an infection with predominant respiratory features caused by the novel coronavirus
SARS-CoV-2. The disease rapidly spread worldwide and was declared a global pandemic on
March 11, 2020 by the World Health Organization (WHO). By July 20, 2020, COVID-19 had
affected more than 14 million people in 188 territories, with more than 608,000 deaths.1 Despite
the incidence and mortality magnitude, how the infection impacts pregnancy or whether
pregnancy and the postpartum period would lead to more vulnerability remain uncertain.2,3 Acc
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Initial case series from China did not identify increased risk of adverse outcomes among obstetric
patients when compared to the general population, as well as no maternal deaths were reported.4,5
However, physiological adaptations in normal pregnancies, mainly cardio-respiratory and
immune, are known to increase the susceptibility of pregnant women to several infectious agents
and viral pneumonia in particular6. Thus, clinicians worldwide remained worried about the impact
of COVID-19 in this population. Subsequent data emerging from Europe and North America also
concluded that pregnant women were at no increased risk of severe COVID-19 or death3,7,8. More
recently, further studies reported higher risk of ICU admission and mechanical ventilation during
pregnancy9,10, as well as the first near miss and maternal deaths cases emerged from Iran, US, UK,
France, Mexico and Spain7–9,11–16.
In Brazil, approximately two months after the first official COVID-19 case was reported, 1,700
deaths among the general population and five maternal deaths had already been documented,
raising concerns that perhaps the pandemic in low- and middle-income countries could pose
additional risks for pregnant women.17 It was hypothesized that higher birth rates, worse
population health status, and poor quality of obstetric care, now competing with constraints
resulting from the pandemics management, would contribute to an increase in the absolute number
of deaths and also in the case fatality rate.17
The present analysis continues the initial investigations17–19 of our group using data from the
Brazilian Ministry of Health Acute Respiratory Distress Syndrome (ARDS) Surveillance System
(ARDS-SS) to describe clinical characteristic and to examine risk factors for death among
COVID-19 cases during pregnancy and the postpartum period in Brazil.
MATERIALS AND METHODS
This is a secondary database, cross-sectional analysis of the ARDS-SS. Data were extracted from
the ARDS-SS, which comprises mandatory notifications of all ARDS cases in the country, from
both public and private units in all states. ARDS-SS was established in 2009, as a response to the
H1N1 pandemic and specific fields to track pregnant and postpartum women has been available
since then20. New specific fields were incorporated to the ARDS Notification Form to gather
information on COVID-19 cases and are included in the database as well. Anonymized data is
made publicly available by the Ministry of Health. Data was abstracted in June 18, 2020 and
inclusion criteria were: i) pregnant or postpartum women; ii) confirmed (nasopharyngeal RT-PCR)
SARS-CoV2 infection or confirmed COVID-19 case based on Brazilian Ministry of Health case Acc
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definition; iii) final outcome (death or cure) recorded in the database; iv) registered from February
26 (date of the first COVID-19 case in the country) to June 18, 2020. We have been monitoring
maternal deaths due to COVID-19 in Brazil since the beginning of the pandemic. We have
published so far preliminary data on subsets of the present sample as they were available in each
publication date17–19,21, the last one including all 124 fatal cases notified until June 18, 2020, as
well as 854 cases who evolved to cure18.
Besides ARDS-SS specific fields indicating whether a case is pregnant or in the postpartum
period, we also hand-searched for mentions to pregnancy or postpartum in an open-ended field
related to other comorbidities or risk factors. Information on gestational age or pregnancy outcome
are not routinely collected by the ARDS-SS (only gestational trimester information is available).
A COVID-19 diagnosis was defined as the final classification of each case in the database
according to the epidemiological investigation performed by the notifying unit. Figure 1 presents
the case selection process, as well as the proportion of cases to whom a SARS-CoV-2 RT-PCR
result was available. Among fatal cases, 95.2% had COVID-19 laboratory confirmation and
80.6% had SARS-CoV-2 RT-PCR results available (serological antibodies and rapid test were
recorded for the other cases). These proportions were 97.4% and 78.7%, respectively, among
survivors.
The main outcome was COVID-19 case fatality rate among ARDS-cases in pregnant and
postpartum women and the following variables were analyzed for each case: age, ethnicity,
pregnancy or postpartum status at notification date, gestational trimester at notification date (for
pregnant cases), comorbidities (diabetes, cardiovascular disease, asthma, obesity), ICU admission
and respiratory support requirement. Pregnancy or postpartum status and gestational trimester at
notification date were assumed to be a proxy of symptoms onset timing, once the Notification
Form collecting this information is usually filled in upon hospital admission due to ARDS.
Comorbidity-related ARDS-SS fields do not allow identification of gestational or pre-gestational
diabetes and hypertension and did not separate heart diseases from hypertensive disorders; thus,
these conditions are grouped under “diabetes” and “cardiovascular disease” variables. For the
present analysis, we interpreted missing data as absence of the specific condition or characteristic.
This assumption was applicable to comorbidities, ICU admission and respiratory support. Overall
missingness for comorbidities on ARDS-SS was previously described by Baqui et al for the
general population22 and by Takemoto et al18 for the obstetric population. Acc
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Core outcome sets and patient involvement requirements are not applicable to this analysis due to
its retrospective, secondary database nature. Brazilian ethical regulations do not require
Institutional Review Board approval for secondary anonymized data analysis.
Sample size calculation was not performed once we included all eligible cases from the
nationwide ARDS-SS database. STATA 12 was used for statistical analyses. Continuous variables
were described using measures of central tendency and dispersion and compared using the Mann-
Whitney test. Categorical variables were described using measures of frequency and compared by
exact Fisher’s and Chi-squared test. Multiple logistic regression with a simultaneous entry method
was used to explore association of demographic and clinical characteristics with risk of death.
Variables with statistically significant differences in hypothesis tests were selected to enter the
model (age data was dichotomized as ≤ or > 35 years). Statistical significance level was set at 0.05
and all p-values were two-tailed.
Funding
This research received no specific grant from any funding agency in the public, commercial, or
not-for-profit sectors.
RESULTS
We identified 978 COVID-19 cases in pregnant or postpartum women in the ARDS-SS with
recorded outcome. The case fatality rate among women with COVID-19 ARDS during pregnancy
and postpartum was 12.7% (124 deaths). Figure 2 illustrates the distribution of cases within the
country with most cases occurring in São Paulo (SP, n=359), Rio de Janeiro (RJ, n=107), Ceará
(CE, n=106), and Amazonas (AM, n=92). Mortality rate among COVID-19 maternal ARDS cases
in these states were: 14.1%, 9.4%, 29.0%, and 5.8% (data not shown).
Demographic and clinical characteristics of fatal and non-fatal cases are shown in Table 1. Non-
survivors were older and symptoms onset occurred more frequently in postpartum. At least one
comorbidity was present in 48.4% of fatal cases compared to 24.9% in survival cases, and the
most common was cardiovascular disease, followed by diabetes. Among women who died, 58.9%
were admitted to ICU, 53.2% had invasive ventilation and 29.0% had no respiratory support.
The multivariate logistic regression showed that the main risk factors for maternal death by
COVID-19 were postpartum at onset of ARDS (OR=2.48; 1.65-3.72), obesity (OR=2.31; 1.10-Acc
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4.84), diabetes (OR=1.82; 1.01-3.28) and cardiovascular disease (OR=1.74; 1.02-2.94), while
white ethnicity had a protective effect (OR=0.58; 0.35-0.99) (Table 2).
DISCUSSION
Main findings
We identified 978 maternal cases of ARDS and 124 maternal deaths due to COVID-19 in Brazil.
Women in our sample were generally young, and the age difference between survivors and non-
survivors was only 2 years although statistically significant. Besides, a significant proportion
(51.6%) of women who died from COVID-19 had no comorbidities or risk factors recorded in the
ARDS-SS database. This seems to indicate that apparently young and healthy women have died
due to COVID-19 complications during pregnancy or just after birth. Among those who had
comorbidities, the most common condition was cardiovascular disease followed by diabetes.
Similar findings have been documented in a systematic review with non-pregnant subjects.23
In our sample, 41.1% of women were not admitted to the ICU and 29.0% did not have records of
any type of respiratory support. These findings may indicate that barriers to access intensive care
may be playing a role in the overwhelming number of COVID-19 maternal deaths in Brazil. A US
Center for Disease Control report examining more than 8,000 pregnant women with COVID-19
and 16 cases of maternal deaths identified an increased risk of hospital admission, admission to
the ICU and mechanical ventilation in pregnant women, although there was no higher risk of
death9. Similar findings were also described in Sweden10, demonstrating that pregnant women
may be more susceptible to COVID-19 complications, but with adequate and timely intensive care
the survival rate could be similar to non-pregnant women.
Obstetric cases of ARDS due to COVID-19 in Brazil are at an increased risk of death if symptoms
onset occurs during the postpartum period, they had obesity, diabetes, or cardiovascular disease.
Similarly, an analysis from Mexico24 identified that having a comorbidity, particularly diabetes,
increases the risk of death among pregnant women with COVID-19. In our sample, being White
was protective against death. Previous finds from UK and US have indicated that pregnant women
from ethnic minority groups are at increased risk of adverse outcomes8,9. Similar findings were
expected in Brazil, where racial disparities in the access to health care are well documented.25
Strengths and limitationsAcc
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Our study is secondary data analysis of an official nationwide database. In Brazil, ARDS cases
due to any cause have been considered of mandatory notification to the Ministry of Health since
2009 and the specific aetiology is recorded, as well as the diagnostic method. Both aspects
contribute to the robustness of our analysis in terms of nationwide representativeness and to the
higher rate of laboratory-confirmed SARS-CoV-2. Additionally, our findings about risk factors for
death are consistent with a previous report from Mexico24 and also with analysis for the general
population23,26. It is important to highlight that the available data refer to COVID-19 ARDS cases
only and that we do not have information on non-ARDS COVID-19 cases in the obstetric
population systematically collected in the country. Also, underreporting of maternal deaths is a
recognized issue in the country.27
Interpretation
According to our findings, the number of COVID-19-related maternal deaths is up to now
surpassing the published available combined figures from other countries28. To our knowledge,
available data on maternal deaths with COVID-19 worldwide officially consisted of 36 deaths
when our data was abstract on June 18, 2020. It is not possible to rule out globally underreported
maternal deaths due to COVID-19. Although maternal mortality is an important health indicator
and is usually strictly monitored worldwide, the data might be incomplete within the pandemic
context. Comparatively, during the H1N1 epidemic in 2009, Brazil had 83 maternal deaths due to
any influenza pneumonia in a 12-month period.29 The number of COVID-19 maternal deaths in
the country in a 3-months period is 49% higher than the figures for H1N1 in the entire 2009 year.
COVID-19 pandemic hit Brazil while the country was still struggling with unacceptably high
maternal death ratio29. Despite possible greater susceptibility to severe acute respiratory
syndromes in pregnant women in general, it is worth mentioning the significant variation in the
number of deaths between different Brazilian States. These findings suggest that negative
outcomes in pregnancy during the COVID-19 pandemic might also be associated with poor
quality obstetric care, social risks and barriers to access health care, once physiological
adaptations and clinical factors are not anticipated to be markedly different across different
geographic regions. Notably, Brazilian’s federal government actions to contain COVID-19
pandemic are being recognized as not only ineffective but also endangering. Against universal
recommendations, the government failed to reinforce the need for social isolation or to provide
universal screening, as well proper investments in health units and supplies.30 Acc
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Currently, the first cause of maternal death and near miss in Brazil is hypertension29,31, and
inflammatory states have been described as relevant etiological hypothesis for both hypertension
and preeclampsia.32 Thus, when hypertension and COVID-19 simultaneously occur, it is possible
to conjecture that inflammatory response may play a role in worsening prognosis, especially
during pregnancy. Another possible explanation may be a combination of the country’s high
prevalence of overweight and obesity with metabolic syndrome,33 considering the same
inflammatory aspect of immune system response to coronavirus. Obesity was associated with
antepartum severe maternal morbidity and may contribute to maternal deaths due its association
with preeclampsia34,35.
The prioritization of COVID-19 cases through the health care systems have been described as
impacting maternal and neonatal outcomes worldwide.36 In Brazil, even before the COVID-19
global pandemic, access to antenatal care faced chronic and complex barriers.25,37 Therefore,
barriers to access routine assessment and testing may lead to delays in receiving proper care,
potentially contributing to maternal deaths. Additionally, Brazilian caesarean rates are historically
high and local data evidenced a three times higher risk of maternal death associated with caesarean
sections.38 In the pandemic context, at least one study already raised awareness of increased risk of
adverse and/or severe features of COVID-19 disease for patients undergoing surgeries.39
The disquieting findings about maternal deaths due to COVID-19 in Brazil are worrisome, since
the country was not able to control the pandemic and the number of new cases and deaths are still
rising. Our data highlights the urgent need for containment measures aimed to the obstetric
population, particularly women with high-risk pregnancies and postpartum women. These
measures should include timely and detailed analysis of each COVID-19-related maternal death
along with COVID-19-related maternal near misses (the latter not even auditable through
Brazilian health information system). . This might allow producing guidelines and local strategies
to improve patients’ journey specifically designed for COVID-19 during pregnancy and
postpartum, to enhance maternal and perinatal outcomes.
A call for action in April 2020 already anticipated that women during pregnancy and postpartum
might be a vulnerable population for COVID-19 not only due to biological or clinical factors, but
also due to social risks.40 We believe that Brazil is currently facing the tragedy of the
aforementioned prediction, and that estimating its real dimension can contribute to reverse the
present disaster.Acc
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CONCLUSION
COVID-19-related maternal deaths in Brazil surpassed worldwide combined published figures.
Negative outcomes of COVID-19 in this population are affected by clinical characteristics, but
social determinants of health and barriers to access proper care seem to play a role. It is urgent to
reinforce containment measures targeting the obstetric population and ensure high quality care
throughout pregnancy and the postpartum period.
DISCLOSURE OF INTERESTS
We declare no competing interests. Completed disclosure of interest forms are available to view
online as supporting information.
ACKNOWLEDGMENTS
The authors would like to thank all members of the Brazilian Group for Studies of COVID-19 and
pregnancy for all efforts in supporting this work.
CONTRIBUTION TO AUTHORSHIP
MLST contributed for study conception and study design, conducted literature search and data
extraction, conducted data analysis and interpretation, wrote the first draft of the paper, reviewed
and approved the final manuscript.
MOM contributed for study conception and study design, conducted literature search and data
extraction, conducted data analysis and interpretation, wrote the first draft of the paper, reviewed
and approved the final manuscript.
CAB contributed for study conception and study design, conducted data analysis and
interpretation, reviewed and provided comments on the first draft, reviewed and approved the final
manuscript.
RK contributed for study conception and study design, conducted data analysis and interpretation,
reviewed and provided comments on the first draft, reviewed and approved the final manuscript.
LARS contributed for study conception and study design
LK contributed for study conception and study design, reviewed and approved the final
manuscript.
EBF contributed for study conception and study design, reviewed and approved the final
manuscript.Acc
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MNP contributed for study conception and study design, conducted data analysis and
interpretation, reviewed and provided comments on the first draft, reviewed and approved the final
manuscript.
CGM contributed for study conception and study design, reviewed and approved the final
manuscript.
CSGD contributed for study conception and study design, reviewed and approved the final
manuscript.
ASOM contributed for study conception and study design, conducted literature search and data
collection, conducted data analysis and interpretation, wrote the first draft of the paper, reviewed
and approved the final manuscript.
MMRA contributed for study conception and study design, wrote the first draft of the paper,
reviewed and approved the final manuscript.
DETAILS OF ETHICS APPROVAL
According to Brazilian ethics regulatory requirements, secondary analysis of publicly available
anonymized data does not require Institutional Review Board ethics approval.
FUNDING
This research received no specific grant from any funding agency in the public, commercial, or
not-for-profit sectors.
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Figure Legends
Figure 1. Case selection flowchart
Figure 2. Geographic distribution of pregnant and postpartum cases with COVID-19 on
ARDS-SS and complete outcome by June 18, 2020
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Table 1. Characteristics of COVID-19 maternal ARDS cases in Brazil (n=978)
Death (n=124) Cure (n=854)
n % n %p-value
Age – median (IQR) 32 (25-37) 30 (24-35) 0.0039*
Postpartum 50 40.3 174 20.4
Pregnancy 74 59.7 680 79.6<0.0001**
1st trimester 2 2.7 55 8.1
2nd trimester 21 28.4 148 21.8
3rd trimester 46 62.2 449 66.0
Unknown 5 6.7 28 4.1
0.1662***
Skin color/ethnicity
White 23 18.5 212 24.8
Black 5 4.0 46 5.4
Yellow 1 0.8 2 0.2
Brown 64 51.6 387 45.3
Indigenous 1 0.8 5 0.6
Missing 30 24.2 202 23.7
0.5013***
Comorbidities or risk factors
Asthma 5 4.0 17 2.0 0.1839**
Cardiovascular disease 26 21.0 91 10.7 <0.0001**
Diabetes 21 16.9 65 7.6 <0.0001**
Obesity 12 9.7 31 3.6 <0.0001**
Any comorbidity or risk factor 60 48.4 213 24.9 <0.0001**
Use of Intensive care
ICU admission 73 58.9 134 15.7 <0.0001**
Invasive ventilation 66 53.2 32 3.7
Non-invasive ventilation 22 17.7 197 23.1
No respiratory support 36 29.0 625 73.2
<0.0001***
* Mann-Whitney test; **Exact Fisher’s test; ***Chi-squared test; SD, standard deviation; ICU,
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Table 2. Multivariate Logistic Regression Analysis of Risk Factors for Maternal Death with
ARDS due to COVID-19
Variables OR (95% CI) p-value
Postpartum at the time of ARDS
notification
2.481 (1.654-3.720) <0.0001
Obesity 2.307 (1.101-4.837) 0.0268
White ethnicity 0.585 (0.346-0.991) 0.0463
Diabetes 1.817 (1.007-3.278) 0.0472
Cardiovascular disease 1.736 (1.024-2.945) 0.0407
Classification table 86.9% correctly classified using enter logistic regression method, Constant = -
2.316. Area under the receiver operating characteristic (ROC) curve [95% CI] = 0.674 [0.643-
0.703]; OR, Odds Ratio; CI, Confidence Interval; ARDS, Acute Respiratory Distress Syndrome
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